A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti-type I IFN-α receptor (IFN-αR) monoclonal antibody, MEDI-546, in a phase I trial in SSc. MEDI-546 suppressed IFN signature in blood and skin of SSc patients in a dose-dependent manner. To bridge clinical indications to SLE, we developed a model incorporating (i) pharmacokinetics (PK) and pharmacodynamics (PD) in SSc patients, (ii) internalization kinetics of MEDI-546/IFN-αR complex, and (iii) the different IFN signatures between SSc and SLE. Simulations predicted that i.v. administration of MEDI-546 at 300- or 1,000-mg monthly doses could suppress IFN signature in blood to levels of healthy subjects in 53 and 68% of SLE patients, respectively. An innovative approach utilizing a novel biomarker characterized the PD of MEDI-546 by modeling and simulation and allowed rapid progression of MEDI-546 from a phase I study in SSc to a randomized, multiple-dose phase II trial.
BACKGROUND AND PURPOSEFor antibody therapies against receptor targets, in vivo outcomes can be difficult to predict because of target-mediated clearance or antigen 'sink' effects. The purpose of this work was to engineer an antibody to the GM-CSF receptor a (GM-CSFRa) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients. EXPERIMENTAL APPROACHWe used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody in vitro before refining the modelling predictions of the eventual dosing in man. Finally, in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development. KEY RESULTSAntibody potency was improved 8600-fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg -1 and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg -1 dosing. CONCLUSIONS AND IMPLICATIONSThis rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals.
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